Complement factor B is critical for sub-RPE deposit accumulation in a model of Doyne honeycomb retinal dystrophy with features of age-related macular degeneration
Open accessAbstract
EFEMP1 R345W is a dominant mutation causing Doyne honeycomb retinal dystrophy/malattia leventinese (DHRD/ML), a rare blinding disease with clinical pathology similar to age-related macular degeneration (AMD). Aged Efemp1 R345W/R345W knock-in mice (Efemp1ki/ki) develop microscopic deposits on the basal side of retinal pigment epithelial cells (RPE), an early feature in DHRD/ML and AMD. Here, we assessed the role of alternative complement pathway component factor B (FB) in the formation of these deposits. RNA-seq analysis of the posterior eyecups revealed increased unfolded protein response, decreased mitochondrial function in the neural retina (by 3 months of age) and increased inflammatory pathways in both neural retina and posterior eyecups (at 17 months of age) of Efemp1ki/ki mice compared with wild-type littermate controls. Proteomics analysis of eye lysates confirmed similar dysregulated pathways as detected by RNA-seq. Complement activation was increased in aged Efemp1ki/ki eyes with an approximately 2-fold elevation of complement breakdown products iC3b and Ba (P < 0.05). Deletion of the Cfb gene in female Efemp1ki/ki mice partially normalized the above dysregulated biological pathway changes and oral dosing of a small molecule FB inhibitor from 10 to 12 months of age reduced sub-RPE deposits by 65% (P = 0.029). In contrast, male Efemp1ki/ki mice had fewer sub-RPE deposits than age-matched females, no elevation of ocular complement activation and no effect of FB inhibition on sub-RPE deposits. The effects of FB deletion or inhibition on Efemp1ki/ki mice supports systemic inhibition of the alternative complement pathway as a potential treatment of dry AMD and DHRD/ML.
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Complement proteins C3 and Factor B (FB) have been found to be essential for drusen formation in mouse models of inherited retinal degeneration.
“In fact, complement proteins C3 and Factor B (FB) have been found to be essential for drusen formation in mouse models of inherited retinal degeneration [119,120,121].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [121]
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- Authors
- Crowley, M. A., Garland, D. L., Sellner, H., Banks, A., Fan, L., Rejtar, T., Buchanan, N., Delgado, O., Xu, Y. Y., Jose, S., Adams, C. M., Mogi, M., Wang, K., Bigelow, C. E., Poor, S., Anderson, K., Jaffee, B. D., Prasanna, G., Grosskreutz, C., Fernandez-Godino, R., Pierce, E. A., Dryja, T. P., & Liao, S.-M.
- Affiliations
- Ophthalmology, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA
- Massachusetts Eye and Ear Infirmary (US)
- Novartis (Switzerland) (CH)
- Analytical Sciences and Imaging, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research , Cambridge, MA 02319 , USA
- Ocular Genomics Institute at Massachusetts Eye and Ear, Harvard Medical School , Boston, MA 02114 , USA
- Corresponding author
- Liao, Sha-Mei
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-08-09
- Volume
- 32
- Issue
- 2
- Pages
- 204-217
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC9840207
- OpenAlex
- W4290793038
- Cited by
- 20
- References
- 58
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 2
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Human Molecular Genetics (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Novartis Institutes for BioMedical Research
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- Malattia Leventinese, factor B, alternative complement pathway, age-related macular degeneration, dry age-related macular degeneration, retinal pigment epithelium, unfolded protein response, mitochondrial dysfunction, ocular inflammation, complement activation, iC3b, BA, complement inhibitors, sex differences, knock-in mice
- MeSH terms
- Animals, Female, Macular Degeneration, Male, Complement Factor B, Retina, Optic Disk Drusen, Mice, Retinal Pigment Epithelium
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